P315: TP53 ALTERATIONS AND MRD REFINE PROGNOSIS OF ADULT KMT2A-REARRANGED B-ALL
Authors: Rathana Kim, Hugo Bergugnat, Florence Pasquier, Emmanuel Raffoux, Lise Larcher, Marie Passet, Cedric Pastoret, Grardel Nathalie, Vahid Asnafi, Eric Delabesse, Aurélie Caye-Eude, Claus Meyer, Rolf Masrschalek, Anne Thiebaut-Bertrand, Marie Balsat, Martine Escoffre, Sabine Blum, Michael Baumann, Anne Banos, Nicole Straetmans, Maria Pilar Gallego Hernanz, Yves Chalandon, Carlos Graux, Thibaut Leguay, Mathilde Hunault, Françoise Huguet, Véronique Lhéritier, Jean Soulier, Nicolas Boissel, Emmanuelle Clappier
Journal: HemaSphere (2023)

Topic: 1. Acute lymphoblastic leukemia - Biology & Translational Research Background: B-cell acute lymphoblastic leukaemia (B-ALL) with a rearrangement involving KMT2A/MLL (KMT2A-r) accounts for 80% of infant B-ALL and 10% of adult cases. This entity has been widely associated with a high risk of relapse and poor outcome in both children and adults. Aims: We set out to refine the prognosis of KMT2A-r B-ALL in adults treated with current intensive regimens, by analysing the impact of co-mutations and minimal residual disease (MRD) on outcome. Methods: Of 1091 Ph-negative B-ALL patients aged 15-59 years treated within the GRAALL-2003/05/14 trials, with available KMT2A-r screening, 141 (12.9%) harboured a KMT2A-r. Targeted sequencing was performed for 97 KMT2A-r B-ALL cases with available diagnostic material to identify additional mutations and copy-number alterations. MRD quantification was done by qPCR of clono-specific immunoglobulin and/or T-cell receptor genes rearrangements (IG/TR). The genomic KMT2A fusion breakpoint (gKMT2A-r) was used as an additional marker for a subset of patients. Cut-off for MRD positivity was set at 10-4. Results: Patients with KMT2A-r B-ALL had a median age of 42.0 years, a male/female ratio of 0.78, high white blood cell counts at diagnosis (median 94.4 G/L) and frequent immature pro-B phenotype (74.8 %). The complete remission (CR) rate was 92.9% and 48.9% of patients received allogeneic stem cell transplantation (allo-SCT) in first CR. At 5 years, the disease-free survival (DFS) and overall survival (OS) rates were 50.3% and 53.3%, respectively. The KMT2A-r partner gene was AFF1 in 121/141 cases (86%). The most frequent co-mutations involved signalling pathway genes (38%), mostly NRAS, KRAS and FLT3. CDKN2A, TP53 and IKZF1 were altered in respectively 14%, 14% and 8% of cases. TP53 alteration was the only genetic feature significantly associated with poorer outcome (DFS, HR=2.2, 95% CI [1.1-4.6], P=0.034; OS, HR=2.7, 95% CI [1.3-5.4], P=0.007) (fig. 1A-B). IG/TR MRD data was available for 77 patients. Of these, 44.2% had positive MRD at end of induction and this was strongly predictive of poorer outcome (DFS, HR=2.7, 95% CI [1.4-5.2], P=0.003; OS, HR=2.9, 95% CI [1.5-6.0], P=0.003) (fig. 1C-D). Studies in infant B-ALL have shown that IG/TR rearrangements could be absent or subclonal in KMT2A-r B-ALL, justifying the use of gKMT2A-r as an MRD marker. Thus, we conducted a retrospective comparative analysis for the 56 patients treated within the GRAALL-2014. 7/56 (13%) patients lacked clonal IG/TR rearrangement for MRD follow-up. Of 39 cases (70%) that could be evaluated for both MRD targets, 9 (16%) presented discrepant results, i.e IG/TR negative and gKMT2A-r positive. The latter had similarly poor survival rates as those positive on both markers (fig. 1D-E). The superiority of gKMT2A-r marker over IG/TR was subsequently validated by Harrell’s C concordance tests demonstrating that gKMT2A-r post-induction MRD predicts outcome with better accuracy than IG/TR MRD (0.68 vs 0.63 for DFS and 0.66 vs 0.62 for OS). Strikingly, patients with negative gKMT2A-r MRD (n=13) after induction course had an excellent outcome, although they did not receive allo-SCT in accordance with the protocol. Summary/Conclusion: Our study establishes the association between TP53 alterations and poor outcome in adult KMT2A-r B-ALL. It also demonstrates the relevance of using gKMT2A-r as MRD marker in adults, allowing the identification of good responders who had excellent survival rates. Altogether, the combination of genetic co-alterations and MRD refines the prognosis of adult KMT2A-r patients by identifying subsets of patients with contrasting outcomes.Keywords: TP53, ALL, Minimal residual disease (MRD), KMT2A